We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II+) CD11b+Ly-6G+ neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II+, CD11b+Ly-6C+ mature monocytes increased modestly throughout the disease course. Amelioration of the clinical disease by TSA treatment was accompanied by diminished abundance of CD11b+Ly-6Gdim activated neutrophils in secondary lymphoid organs and their influx into the spinal cord without affecting monocytes. Interestingly, the co-inhibitory ligand CD274+ (PD-L1+) but not CD275+ (ICOS-L+), CD39+ or CD11c+ dendritic cells were decreased in the peripheral lymphoid compartment of drug treated mice. Thus, in addition to myelin-specific T cell tolerance induction observed previously, selective repression of mature neutrophils and PD-L1+ cells is critically involved in the epigenetic regulation of P-EAE.